title: Parkin deficiency increases vulnerability to inflammation-related nigral degeneration.
abstract: The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher plasma concentrations of a number of proinflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient (parkin-/-) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient, and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin-/- mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin-/- mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin-/- mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in preclinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.
authors.affiliation: Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA.
authors.forename: Tamy C
authors.initials: TC
authors.lastname: Frank-Cannon
authors.forename: Thi
authors.initials: T
authors.lastname: Tran
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Ruhn
authors.forename: Terina N
authors.initials: TN
authors.lastname: Martinez
authors.forename: John
authors.initials: J
authors.lastname: Hong
authors.forename: Marian
authors.initials: M
authors.lastname: Marvin
authors.forename: Meagan
authors.initials: M
authors.lastname: Hartley
authors.forename: Isaac
authors.initials: I
authors.lastname: Treviño
authors.forename: Daniel E
authors.initials: DE
authors.lastname: O'Brien
authors.forename: Bradford
authors.initials: B
authors.lastname: Casey
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Malú G
authors.initials: MG
authors.lastname: Tansey
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D015999:Multivariate Analysis; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011134:Polysaccharides; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D045442:Rotarod Performance Test; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency*; D000099156:Superoxide Dismutase 2
chemical_list: D016207:Cytokines; D004298:Dopamine; D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D052247:Nitric Oxide Synthase Type II; D011134:Polysaccharides; D013482:Superoxide Dismutase; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; D000099156:Superoxide Dismutase 2; C495636:Nfe2l2 protein, mouse; C111567:parkin protein